Therapeutic Angiogenesis by Universal Donor Endometrial Regenerative Cells (ERC) Abstract The proposed study seeks to develop a practical, off the shelf, universal donor, cell therapy for an advanced form of peripheral artery disease termed "critical limb ischemia" (CLI). The major problem facing CLI patients is lack of proper circulation to the extremities. Although a basal level of collateral vessel formation has been documented in these patients, in many cases it is insufficient to prevent amputation. Methods of augmenting the process of collateral vessel formation through administration of angiogenic cytokines have largely failed clinically [1-3]. One explanation for this has been that cytokine administration was performed under conditions that were not physiological, both in terms of sequence and combinations. A more therapeutically promising method has been administration of autologous stem cells which secrete angiogenic cytokines under what appears to be more physiological conditions. Numerous clinical trials have demonstrated benefit using bone marrow and mobilized peripheral blood stem cell populations, which are reviewed in the following reference [4]. Unfortunately, adult autologous cells display reduced angiogenic capacity, especially in CLI patients [5, 6]. Additionally, the procedures for harvesting stem cells from the bone marrow or peripheral blood are considered to be dangerous in patients with CLI due to existing comorbidities [7, 8]. From a practical perspective autologous therapy can only be performed at specialized centers which have certified clean rooms and experience with cell processing. A novel stem cell population termed "endometrial regenerative cells" (ERC) has been identified by Medistem, Inc., that the company is developing with General BioTechnology, LLC as a "universal donor" population. To date this collaboration has resulted in a cell population that inhibits inflammatory responses, do not elicit T cell reactivity, and can survive in allogeneic and xenogeneic hosts in absence of immune suppression both in vitro and in vivo. Given the large amount of angiogenic growth factor secretion and ability to stimulate angiogenesis, the ERC may be a commercially viable substitute for autologous stem cell implantation that circumvents the problems of: extraction, age and disease associated stem cell dysfunction, and requirement for clean room facilities at the point of care. The current proposal seeks support to expand on existing efficacy evaluation so as to permit entry into Phase Ib/II clinical trials. PUBLIC HEALTH RELEVANCE: The project aims to augment existing safety and manufacturing data to submit a Phase Ib/II IND for treatment of critical limb ischemia using a novel adult stem cell population developed by Medistem termed Endometrial Regenerative Cells (ERC). Existing data demonstrates ERC are potently angiogenic, anti-inflammatory, and can be used in a "universal donor" manner, thus providing an easy to use, off the shelf cellular therapy for a condition that lacks therapeutic options besides amputation.